title: Redox regulation of interleukin-4 signaling.
abstract: The physiologic control of cytokine receptor activation is primarily mediated by reciprocal activation of receptor-associated protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Here, we show that immediately after ligand-dependent activation, interleukin (IL)-4 receptor generated reactive oxygen species (ROS) via phosphatidylinositol 3-kinase-dependent activation of NAD(P)H oxidase (NOX)1 and NOX5L. ROS, in turn, promoted IL-4 receptor activation by oxidatively inactivating PTP1B that physically associated with and deactivated IL-4 receptor. However, ROS were not required for the initiation of IL-4 receptor activation. ROS generated by other cytokine receptors, including those for erythropoietin, tumor necrosis factor-alpha, or IL-3, also promoted IL-4 signaling. These data indicate that inactivation of receptor-associated PTP activity by cytokine-generated ROS is a physiologic mechanism for the amplification of cytokine receptor activation in both cis and trans, revealing a role for ROS in cytokine crosstalk.
authors.affiliation: Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Sharma
authors.forename: Rikhia
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Booki
authors.initials: B
authors.lastname: Min
authors.forename: Michel L
authors.initials: ML
authors.lastname: Tremblay
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Kawahara
authors.forename: J David
authors.initials: JD
authors.lastname: Lambeth
authors.forename: S Jaharul
authors.initials: SJ
authors.lastname: Haque
mesh_terms: D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D003001:Cloning, Molecular; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D051379:Mice; D019255:NADPH Oxidases / Q000378:metabolism*; D010084:Oxidation-Reduction; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011972:Receptor, Insulin / Q000378:metabolism; D019948:Receptors, Interleukin-4 / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D015847:Interleukin-4; D019255:NADPH Oxidases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D017382:Reactive Oxygen Species; D011972:Receptor, Insulin; D019948:Receptors, Interleukin-4; C081827:insulin receptor serine kinase